Plasma triglyceride is associated with the recurrence of atrial fibrillation after radiofrequency catheter ablation: A retrospective study

Abstract Background The purpose of this study was to explore the association between triglycerides (TGs) and the risk of atrial fibrillation (AF) recurrence. Methods and Results Included were adult patients with AF who underwent radiofrequency catheter ablation in the Affiliated Changzhou Second People's Hospital of Nanjing Medical University. The enrolled patients were divided into the AF recurrence group and the sinus rhythm (SR) maintenance group. The univariate Cox regression analysis and Kaplan–Meier survival curve were performed estimate the association between TG and the risk of AF recurrence. Of the 402 patients, 79 (19.7%) experienced recurrence of AF after ablation. The TG level was significantly higher in the AF recurrence group than in the SR‐maintaining group. Patients were grouped by quartile of TG levels, with Quartile 1 and Quartile 2 defined as the low concentration group, Quartile 3 as the moderate concentration group, and Quartile 4 as the high concentration group. Multivariate Cox regression analysis showed that the moderate concentration group (p = .02, hazard ratio [HR]: 2.331, 95% confidence interval [CI]: 1.141–4.762) and high concentration group (p = .007, HR: 2.873, 95% CI: 1.332–6.199) were associated with an increased risk of AF recurrence compared with the low concentration group. The median follow‐up was 1.17 years, it is indicated that a higher risk of recurrent AF was observed in the moderate concentration and high concentration group (log‐rank: χ 2 = 7.540, p = .023). Conclusion Our data suggest that an elevated TG level measured before catheter ablation is associated with an increased risk of AF recurrence.

recurrent AF was observed in the moderate concentration and high concentration group (log-rank: χ 2 = 7.540, p = .023).

Conclusion:
Our data suggest that an elevated TG level measured before catheter ablation is associated with an increased risk of AF recurrence.

| INTRODUCTION
Atrial fibrillation (AF), the most common arrhythmia in clinical practice, brings with increased risk of stroke, heart failure, and other heart-related complications.In 2017, approximately 304.6 million new cases of AF were confirmed worldwide. 1Current guidelines recommend catheter ablation to improve the quality of life in patients with symptomatic and antiarrhythmic drug-refractory AF. 2 However, recurrence of arrhythmia after catheter ablation is common, with a rate of about 26.4% at 12 months and up to 30% beyond 12 months after catheter ablation. 3,4ny mechanisms underlie the recurrence of AF, including lipid metabolism.6][7] However, others reported no correlation between TG levels and the risk of AF. 8,9 This controversy may arise from bias in sample sizes.TGs, components of triglycerides-rich lipoproteins, are insoluble in water but soluble in the blood after binding to apolipoproteins.Elevated TG level is a risk factor for cardiovascular disease. 103][14][15] We suspect that plasma TG level is also associated with early recurrence of AF.Our study aimed to investigate the effect of plasma TG level on AF recurrence after catheter ablation.

| Medical characteristic data collection
Before catheter ablation, plasma was sampled for laboratory tests.
Standardized case report forms were used to collect personal and medical characteristic data at baseline, including information about demographics, lifestyle habits, medical history, and current medications.According to current guidelines, AF is divided into paroxysmal (spontaneous termination of AF within 48 h) or persistent (lasting more than 7 days, including AF terminated by cardioversion after 7 days or more).The study flowchart is illustrated in Supporting Information S1: Figure 1.

| Catheter ablation
For catheter ablation, an electrode catheter was inserted into the heart by puncturing through the femoral vein, femoral artery, or subclavian vein under X-ray angiography.The site of the abnormal structure causing tachycardia was located and then ablated by a highfrequency current of 100 kHz, 5 MHz that generated a high temperature in a small range.Ablation strategies, including galvanic pulmonary venous isolation, tricuspid isthmus ablation, and left atrial linear ablation, were determined for each patient at the discretion of the surgeon.

| Follow-up and outcome
Patients were followed up for at least 12 months by physical examination, 24-h Holter, or 48-h Holter in the outpatient clinic.
T A B L E 1 Baseline information of SR maintenance patients and AF recurrence patients.The recurrence of AF or atrial tachycardia lasting more than 30 s was defined as the primary study endpoint.AF episodes within 3 months to 1 year after catheter ablation are defined as recurrence. 3Each patient received monthly ECG for 6 months after surgery, and telephone interview every month for reporting discomfort after 1 year.

| Statistical analysis
The statistical analysis was performed using  level, while the white blood cell count and free thyroxine level were significantly reduced (Table 1).As shown in Table 1, there was no significant difference in catheter ablation-related indicators between the SR maintenance group and the AF recurrence group.In addition, we selected TCH, LDL-C, and TG from the lipid index as the objects for box plot analysis.Compared with the SR maintenance group, the TG level in the AF recurrence group was significantly increased, while there was no significant difference in TCH and LDL-C levels (Figure 1).

From
In the univariate analysis, only BMI, platelet count, TG level, and TSH level were significantly associated with AF recurrence (Table 2).
Include the above variables in a multivariate analysis.1.141-4.762)and the high concentration group (p = .007,HR: 2.873, 95% CI: 1.332-6.199)were associated with an increased risk of AF recurrence compared with the low concentration group (Table 3).
The median follow-up was 1.17 years, Kaplan-Meier survival curve showed a higher risk of recurrence of AF was observed in the moderate concentration and high concentration groups (log-rank: χ 2 = 7.540, p = .023)(Figure 2).

| DISCUSSION
The main findings of this study are as follows: (1) In this retrospective analysis of patients with AF undergoing catheter ablation, we for the first time uncovered that the TG level was significantly higher in the AF recurrence group than in the SR-maintaining group.( 2 T A B L E 3 Hazard ratios for recurrent AF after catheter ablation according to TG quartiles and continuous TG levels.were adjusted, it also indicated that the highest TG level group had a 2.873-fold higher risk of AF recurrence than the lowest TG group.(3) Finally, a higher risk of AF recurrence was observed in the moderate and high TG concentration groups.These results suggest that a good control of plasma TG levels in AF patients before catheter ablation may reduce the risk of postoperative recurrence of AF.
The recurrence of AF after ablation therapy may be associated with several mechanisms, including lipid metabolism.Recent studies have found that lipoprotein(a) (Lp(a)), HDL-c, VLDL-c, and TG are metabolized together at high TG levels. 16,17In addition, postprandial lipoprotein(a) elevates with the levels of plasma TGs, 18 suggesting that TGs are closely related to lipoprotein(a).0][21] Lp(a) has also been found as a potential causal mediator in the development of AF. 22 A recent large retrospective cohort study has shown that circulating Lp(a) level is inversely correlated with the risk of AF development. 23,24In addition, a study suggests that the amount of unsaturated fatty acids in TGs is positively correlated with the expression of cardiac remodeling markers, including left atrial diameter, maximum volume, emptying volume, left ventricular ejection fraction, and LA contractile force. 25ese studies suggest that lipid metabolism may be involved in the occurrence of AF by altering the structure of the heart.Since the recurrence rate of AF remains high within 12 months of catheter ablation, 28,29 continued treatment and regular follow-up after surgery are required.Our study provides a potential therapeutic target to improve the success rate of ablation.High TG level appears to be a risk factor for recurrent AF, and should be focused in clinical management.Another study also showed a positive correlation between elevated TG level and ischemic stroke in patients with AF. 30 These data indicate that TG level may be controlled to reduce the risk of AF recurrence after radiofrequency ablation.

| LIMITATION
There are several limitations in the current study.First, patient recruitment in this study started in 2018, and ablation techniques have been upgraded since then, which may have an impact on surgical success. 31,32Second, TGs are related to dietary style.Several institutions including the American Heart Association, the European Atherosclerosis Society, and the Danish Society of Clinical Chemistry, now commend nonfasting lipid examination, but all our data were collected from patients fasting before ablation surgery, which may have affected the study results. 4,33Third, although we proposed a threshold of TGs, it did not achieve a desired effect.Finally, this study evaluated outcomes over 12 months after ablation, and further studies are needed to assess AF recurrence beyond 12 months.

| CONCLUSION
Our data suggest that an elevated TG level measured before catheter ablation is associated with an increased risk of AF recurrence.
Therefore, a good control of plasma TG levels in AF patients before catheter ablation may reduce the risk of postoperative recurrence of AF.

AUTHOR CONTRIBUTIONS
This manuscript was drafted by Qingqing Gu, Ye Deng, and Jun Wei.
Included were adult patients with persistent AF and paroxysmal AF who underwent their first radiofrequency catheter ablation in the Affiliated Changzhou Second People's Hospital of Nanjing Medical University from April 29, 2018 to June 7, 2021.The study was approved by the Ethics Committee of Changzhou Second People's Hospital (No. KY325-01), and was performed in accordance with the Helsinki Declaration.Written informed consent was obtained from all patients.Inclusion criteria: adults aged 18-80 years; patients examined with 12-lead electrocardiogram (ECG) or Holter monitoring for AF; patients with persistent and paroxysmal AF; patients having not taken class I or III antiarrhythmic drugs; patients with symptomatic persistent AF who showed ineffectiveness or intolerance to antiarrhythmic drugs; Exclusion criteria: left atrial anteroposterior diameter >60 mm, left atrial appendage thrombosis, structural cardiac disorders (i.e., severe aorta, tricuspid or mitral valve malformations, tetralogy of Fallot, ventricular and atrial septal defects), psychiatric disorders, septic shock, glomerular filtration rate <30 mL/min, abnormal thyroid function, and severe pericardial effusion or tamponade.
April 29, 2018 to June 7, 2021, a total of 450 subjects with AF were recruited.All patients completed at least one follow-up visit for at least 12 months.Forty-eight patients were lost to follow-up at 12 months of follow-up, leaving them out of the analysis.Of the 402 patients, 79 (19.7%) experienced recurrence of AF after ablation.AF episodes within 3 months to 1 year after catheter ablation were defined as recurrence.Patients were divided into the AF recurrence and the SR maintenance groups.Compared with the SR maintenance group, the AF recurrence group showed a significant increase in red blood cell count, TG level, and thyroid-stimulating hormone (TSH)

F I G U R E 1
Comparison of TCH, LDL-C, and TG levels in two groups.Box plots represent median levels with 25th and 75th percentiles of the value of variables.AF, atrial fibrillation; LDL-C, low-density lipoprotein cholesterol; SR, sinus rhythm; TCH, total cholesterol; TG triglycerides.

F
I G U R E 2 Kaplan-Meier curves for AF recurrence across quartile of TG.It was divided into four groups, Quartile 1 and Quartile 2 defined as the low concentration group (TG < 1.28 mg/L), Quartile 3 as the moderate concentration group (1.28 ≤ TG < 1.89 mg/L), and Quartile 4 as the high concentration group (TG ≥ 1.89 mg/L).AF, atrial fibrillation; TG, triglyceride.
The specific explanation of the mechanism by which TG functions on cardiac structure and conduction is as follows.A recent basic study has shown that downregulation of adipose triglyceride lipase (ATGL) can promote atrial structure and electrical remodeling, thereby increasing the incidence of AF.26 ATGL, a key enzyme, promotes the degradation of TGs in cells and participates in lipid breakdown metabolism,27 suggesting the correlation between TG and AF.A mouse model of myocardial cell-specific ATGL overexpression has shown that in addition to a decrease in TG content in myocardial cells, myocardial cell-specific ATGL overexpression can also improve energy metabolism, systolic function, and cardiac remodeling in healthy hearts.These studies suggest that interrelated mechanisms underlie AF induced by TG and ATGL.
Data were statistically analyzed by Qingqing Guand Dabei Cai.Data were statistically analyzed by Tingting Xiao and Yu Wang.The text was polished by Ye Deng and Li Deng.This study was conceived and designed by Ling Sun, Qingjie Wang, and Yuan Ji.All authors reviewed the manuscript.
Univariate and multivariate Cox proportional hazards regression analysis of AF recurrence.
Model 1 was not adjusted, Model 2 adjusted for age and sex, and Model 3 adjusted for age, sex, body mass index, platelet level, history of hypertension, history of heart failure, and type of AF.According to the TG quartile, it was divided into four groups, Quartile 1 and Quartile 2 defined as the low concentration group (TG < 1.28 mg/L), Quartile 3 as the moderate concentration group (1.28 ≤ TG < 1.89 mg/L), and Quartile 4 as the high concentration group (TG ≥ 1.89 mg/L).